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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y VO L . 7 4 , N O . 1 4 , 2 0 1 9

ª 2 0 1 9 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N

C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

T H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .

ORIGINAL INVESTIGATIONS

Cardiac Magnetic Resonance StressPerfusion Imaging for Evaluation ofPatients With Chest Pain

Raymond Y. Kwong, MD, MPH,a Yin Ge, MD,a Kevin Steel, DO,b Scott Bingham, MD,c Shuaib Abdullah, MD,d

Kana Fujikura, MD, PHD,a Wei Wang, PHD,e Ankur Pandya, PHD,f Yi-Yun Chen, MD, MPH,a J. Ronald Mikolich, MD,g

Sebastian Boland, BS, MBA,g Andrew E. Arai, MD,h W. Patricia Bandettini, MD,h Sujata M. Shanbhag, MD, MPH,h

Amit R. Patel, MD,i Akhil Narang, MD,i Afshin Farzaneh-Far, MD, PHD,j Benjamin Romer, MD,j John F. Heitner, MD,k

Jean Y. Ho, BA,k Jaspal Singh, BA,k Chetan Shenoy, MD,l Andrew Hughes, BS,l Steve W. Leung, MD,m

Meera Marji, MD, MPH,m Jorge A. Gonzalez, MD,n Sandeep Mehta, MD,n Dipan J. Shah, MD,o Dany Debs, MD,o

Subha V. Raman, MD,p Avirup Guha, MD,p Victor A. Ferrari, MD,q Jeanette Schulz-Menger, MD,r

Rory Hachamovitch, MD, PHD,s Matthias Stuber, PHD,t Orlando P. Simonetti, PHDp

ABSTRACT

ISS

Fro

Ra

Sa

SofDe

of

BACKGROUND Stress cardiac magnetic resonance imaging (CMR) has demonstrated excellent diagnostic and

prognostic value in single-center studies.

OBJECTIVES This study sought to investigate the prognostic value of stress CMR and downstream costs from

subsequent cardiac testing in a retrospective multicenter study in the United States.

METHODS In this retrospective study, consecutive patients from 13 centers across 11 states who presented with a chest

pain syndrome and were referred for stress CMR were followed for a target period of 4 years. The authors associated CMR

findings with a primary outcome of cardiovascular death or nonfatal myocardial infarction using competing risk-adjusted

regression models and downstream costs of ischemia testing using published Medicare national payment rates.

RESULTS In this study, 2,349 patients (63 � 11 years of age, 47% female) were followed for a median of 5.4 years.

Patients with no ischemia or late gadolinium enhancement (LGE) by CMR, observed in 1,583 patients (67%), experienced

low annualized rates of primary outcome (<1%) and coronary revascularization (1% to 3%), across all years of study

follow-up. In contrast, patients with ischemiaþ/LGEþ experienced a >4-fold higher annual primary outcome rate and a

>10-fold higher rate of coronary revascularization during the first year after CMR. Patients with ischemia and LGE both

negative had low average annual cost spent on ischemia testing across all years of follow-up, and this pattern was similar

across the 4 practice environments of the participating centers.

CONCLUSIONS In a multicenter U.S. cohort with stable chest pain syndromes, stress CMR performed at experienced

centers offers effective cardiac prognostication. Patients without CMR ischemia or LGE experienced a low incidence

of cardiac events, little need for coronary revascularization, and low spending on subsequent ischemia testing.

(Stress CMR Perfusion Imaging in the United States [SPINS]: A Society for Cardiovascular Resonance Registry Study;

NCT03192891) (J Am Coll Cardiol 2019;74:1741–55) © 2019 The Authors. Published by Elsevier on behalf of the American

College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.

org/licenses/by-nc-nd/4.0/).

N 0735-1097 https://doi.org/10.1016/j.jacc.2019.07.074

m the aNoninvasive Cardiovascular Imaging Section, Cardiovascular Division, Department of Medicine and Department of

diology, Brigham and Women’s Hospital, Boston, Massachusetts; bCardiology Division, San Antonio Military Medical Center,

n Antonio, Texas; cRevere Health, Provo, Utah; dVeterans Administration North Texas Healthcare System, University of Texas

uthwestern Medical Center, Dallas, Texas; eDivision of Sleep Medicine, Brigham andWomen’s Hospital, Boston, Massachusetts;

partment of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; gDepartment

Cardiovascular Medicine, Sharon Regional Health System, Sharon, Pennsylvania; hNational Heart, Lung, and Blood Institute,

ABBR EV I A T I ON S

AND ACRONYMS

CA = coronary angiography

CABG = coronary artery bypass

graft

CAD = coronary artery disease

CMR = cardiac magnetic

resonance imaging

LGE = late gadolinium

enhancement

MI = myocardial infarction

PCI = percutaneous coronary

intervention

XCA = x-ray coronary

angiography

National In

Illinois; jDiv

Brooklyn M

Medical Sc

Kentucky,

DeBakey H

Ohio State

Pennsylvan

Research C

Cleveland,

SPINS Regi

Siemens H

cular Magn

analysis, in

Imaging. D

Magnetic R

the Speake

Bayer. Dr. S

institutiona

contents of

Manuscript

Kwong et al. J A C C V O L . 7 4 , N O . 1 4 , 2 0 1 9

Stress CMR Registry for Prognosis and Costs in the United States O C T O B E R 8 , 2 0 1 9 : 1 7 4 1 – 5 5

1742

R andomized multicenter studies (1–3)have demonstrated the high accu-racy of vasodilator stress cardiac

magnetic resonance imaging (CMR) indetecting coronary stenoses and in esti-mating impaired flow reserve (4) in coronaryartery disease (CAD). Stress CMR has alsobeen shown in many studies to be an effec-tive cardiac prognosticating method for pa-tients presenting with chest painsyndromes (5–8). The American College ofCardiology Foundation and American HeartAssociation have recommended stress CMRas an appropriate test for evaluation ofsymptomatic patients with intermediate to

high pre-test probability for CAD (9). However, stressCMR remains an underutilized method in the UnitedStates. Here we present the results of the SPINS(Stress CMR Perfusion Imaging in the United States:A Society for Cardiovascular Resonance RegistryStudy) SCMR (Study of the Society for CardiovascularMagnetic Resonance) registry. SPINS is a multicenterobservational study of patients with stable chestpain syndromes designed to evaluate the long-termperformance of stress CMR for cardiovascularprognosis and to investigate the cost of additionaldownstream cardiac testing following the index stressCMR.

SEE PAGE 1756

METHODS

REGISTRY DESIGN AND PATIENT POPULATION.

Goals and infrastructures of the SCMR registry havebeen described previously (10). SPINS is a study of the

stitutes of Health, Bethesda, Maryland; iCardiology Division, Dep

ision of Cardiology, University of Illinois at Chicago, Chicago, Illin

ethodist Hospital, Brooklyn, New York; lCardiovascular Division

hool, Minneapolis, Minnesota; mGill Heart and Vascular Institute

Lexington, Kentucky; nDivision of Cardiology and Radiology, Scr

eart and Vascular Center, Houston, Texas; pDivision of Cardiovasc

University, Columbus, Ohio; qCardiovascular Division, Perelman

ia, Philadelphia, Pennsylvania; rCharité, Medical Faculty of th

enter, Berlin, and Helios Clinics, Cardiology, Berlin, Germany; sDi

Ohio; and the tDepartment of Radiology, University Hospital, U

stry was funded by the Society for Cardiovascular Magnetic Res

ealthineers (Erlangen, Germany) and Bayer AG (Leverkusen, Germ

etic Resonance provided financial support for the study but d

terpretation, or manuscript drafting. Dr. Arai has research agreem

r. Bandettini is the principal investigator of one of the Bayer

esonance Imaging to Detect Coronary Artery Disease) sites. Dr. Pa

rs Bureau of Astellas. Dr. Schulz-Menger has research agreements

tuber has received nonmonetary research support form Siemens H

l research support from Siemens. All other authors have repor

this paper to disclose.

received March 8, 2019; revised manuscript received July 8, 201

SCMR registry and is retrospective in design. SPINSaimed to test the primary hypothesis that evidence ofischemia or infarction characterized by CMR provideseffective cardiovascular risk stratification in patientswith chest pain syndromes who are at intermediate tohigh pre-test likelihood of significant coronary dis-ease. The study aimed to enroll consecutive patientswho underwent a clinical vasodilator stress CMR inthe United States. Inclusion criteria were: 1) age be-tween 35 and 85 years at the time of CMR; 2) referralfor evaluation of chest pain, dyspnea, abnormalelectrocardiogram, or other clinical presentation thatraised a suspicion of myocardial ischemia as deter-mined by the treating clinician; and 3) presence of atleast 2 of the following coronary risk factors: age >50years for male or >60 years for female subjects; dia-betes mellitus requiring medical treatment; chronichypertension requiring treatment; hypercholester-olemia on medical treatment; family history of pre-mature CAD defined as diagnosis in a first-degreemale relative #55 years old or female relative #65years old; body mass index $30 kg/m2; medicallydocumented peripheral vascular disease; and historyof percutaneous coronary intervention (PCI) ormyocardial infarction (MI). Exclusion criteria werehistory of coronary artery bypass graft (CABG), recent MIwithin 30 days preceding the index CMR study, severe-grade valvular heart disease, nonischemic cardiomyop-athy with a left ventricular ejection fraction <40%,infiltrative or hypertrophic cardiomyopathy, constrictivepericarditis, active pregnancy, competing medicalillnesses with expected survival <2 years, and knowninability to follow-up. Vasodilator stress includedthe use of intravenous infusion of adenosine, intra-venous bolus of regadenoson, or dipyridamole.

artment of Medicine, University of Chicago, Chicago,

ois; kDivision of Cardiology, New York Presbyterian-

, Department of Medicine, University of Minnesota

, Division of Cardiovascular Medicine, University of

ipps Clinic, La Jolla, California; oHouston Methodist

ular Medicine, Department of Internal Medicine, The

School of Medicine, Hospital of the University of

e Humboldt University, Experimental and Clinical

vision of Cardiovascular Medicine, Cleveland Clinic,

niversity of Lausanne, Lausanne, Switzerland. The

onance, using a research grant jointly sponsored by

any). These sponsors to the Society for Cardiovas-

id not play a role in study design, data collection,

ents with Siemens, Bayer, and Circle Cardiovascular

-sponsored GadaCAD2 (Gadavist-Enhanced Cardiac

tel has received a research grant from and served on

with Siemens; and serves on the Advisory Board of

ealthineers. Drs. Raman and Simonetti both receive

ted that they have no relationships relevant to the

9, accepted July 11, 2019.

J A C C V O L . 7 4 , N O . 1 4 , 2 0 1 9 Kwong et al.O C T O B E R 8 , 2 0 1 9 : 1 7 4 1 – 5 5 Stress CMR Registry for Prognosis and Costs in the United States

1743

SELECTION OF ENROLLING CENTERS AND CMR

METHODS. An enrolling center was required to:1) have an active clinical vasodilator stress CMRperfusion imaging program ongoing for at least 10years; 2) contribute between 100 and 500 consecutivepatients who underwent a vasodilator stress CMRperfusion study between January 1, 2008, andDecember 31, 2013, so that at least 4 years of clinicalfollow-up could be achieved at study conclusion; and3) have access to electronic medical records. Eachcenter was also required to have all CMR scansinterpreted by a Core Cardiology Training Symposiumlevel II or III reader, with at least 1 Core CardiologyTraining Symposium level III supervising reader.Enrolling centers must have performed CMR studiesusing either a 1.5-T or a 3-T scanner and pulse se-quences for stress perfusion, cine, and late gadolin-ium enhancement (LGE) imaging of infarction.Enrolling centers were also required to have reportedthe myocardial extent of abnormal stress perfusionand LGE according to the 16-segment or 17-segmentAmerican Heart Association nomenclature. At eachparticipating site, local institutional review boardapproval was obtained to conduct this clinical follow-up study with a waiver of written informed consent.

SAMPLE SIZE CALCULATION. Sample size of thestudy was calculated to accrue at least 150 cases of all-cause death or acute MI for the purpose of deter-mining the prognostic value of ischemia by stressCMR with adjustment for up to 10 known clinical riskvariables. Based on a prior publication (8), prevalenceof ischemia on stress CMR for the study cohort wasestimated to be 23%. Incidence rates of all-causedeath or acute MI were estimated to be 0.5% and6.0% per year in patients with absence and presenceof ischemia, respectively. Over a 4-year follow-up, atleast 124 of 506 patients with ischemia and 36 of 1,694patients without ischemia, were expected to havedied or experienced an acute MI, thus an estimatedtarget sample size of approximately 2,200 patientswas needed to yield a power of 80% with an alphaerror of 5% to detect a difference of >20% for theprimary outcome between the patient groups with anormal versus abnormal stress CMR.DATA COLLECTION. Enrolling centers entered allstudy-related protected health information–free datainto the CMR Cooperative encrypted web-baseddatabase (CMRcoop) for GCMR (Global CMR Regis-try). Clinical variables collected included patient de-mographics, clinical history (prior heart disease andcoronary risk factors), and study indication. CMRvariables included left ventricular volumes and di-mensions, and stress perfusion and LGE (both re-ported as presence or absence on a segmental basis)

using the American Heart Association segmentalmodels. A stress perfusion defect was consideredpresent if it was densest in the endocardium with atransmural gradient across the wall thickness, per-sisted beyond peak myocardial enhancement and forseveral R-R intervals, and conformed to a coronaryarterial distribution. Inducible ischemia (ischemiaþ)was defined as the presence of a stress perfusiondefect, in absence of matching LGE, in $1 segment(11). MI was defined as the presence of LGE (LGEþ)conforming to infarction in $1 segment. Mild, mod-erate, and severe defects were defined as theinvolvement of 1 to 2, 3 to 5, and $6 myocardialsegments, respectively. To determine the diagnosticvalue of stress CMR, we collected the CMR in-terpretations as reported by center readers at thetime of study performance. For quality assurance,each center randomly selected 10% of its CMR studiesand submitted the images for blinded interpretationby the CMR core lab at the Brigham and Women’sHospital to evaluate core lab versus center agree-ment. Information regarding performance of allsubsequent noninvasive tests for CAD during thefollow-up period, including exercise stress testing,stress echocardiography, nuclear perfusion imaging,coronary computed tomographic angiography, repeatstress CMR, and invasive x-ray coronary angiography(XCA) was collected.STUDY ENDPOINTS. All centers were instructed toobtain clinical follow-up data on all enrolled patientsfor at least 4 years after the index stress CMR. Clinicalfollow-up used both electronic medical records anddirect patient contact with either a standardizedchecklist questionnaire or scripted telephone inter-view. Study investigators were trained during theinitiation period, by group webinars and study doc-uments, on specific definitions of all key variablesrequired on the web-based database. All outcomevariables and their standardized published clinicaltrial definitions were posted on the web database (12).Follow-up data was verified by each site’s principalinvestigator. In the final 6 months of the studyperiod, a data quality report was generated by thedata-coordinating center in Boston and sent weeklyto each site. Primary outcome was defined as cardio-vascular death or nonfatal MI. Secondary outcomewas defined by a composite of cardiovascular death,nonfatal MI, hospitalization for unstable angina orcongestive heart failure, and late unplanned CABG.Deaths were categorized as cardiovascular, cancer, orcause unknown. Cardiovascular deaths were deathspreceded by an acute MI, malignant ventriculararrhythmia, or decompensated heart failure. Acute MIdiagnosis required chest pain or anginal equivalent

TABLE 1 Demographics and Baseline Characteristics

Overall(N ¼ 2,349)

No Ischemia orLGE (n ¼ 1,583)

Ischemia orLGE (n ¼ 766) p Value

Clinical data

Follow-up, yrs 5.4 (4.6–6.8) 5.5 (4.6–6.9) 5.3 (4.3–6.5) <0.001

Age, yrs 63 � 11 62 � 11 63 � 11 0.61

Female 1,104 (47.0) 821 (52.0) 283 (37.0) <0.001

BMI, kg/m2 31 � 7 31 � 7 30 � 7 <0.001

No. of cardiac risk factors 3 (2–4) 3 (2–4) 4 (3–5) <0.001

Risk factors*

Hypertension 1,843 (78.0) 1,196 (76.0) 647 (85.0) <0.001

Hypercholesterolemia 1,647 (70.0) 1,053 (67.0) 594 (78.0) <0.001

Diabetes mellitus 664 (28.0) 409 (26.0) 255 (33.0) <0.001

Significant smoking, >10 pack-yrs 757 (32.0) 457 (29.0) 300 (40.0) <0.001

History of premature CAD in first-degree relative 761 (34.0) 495 (32.0) 266 (37.0) 0.03

CAD Consortium score, basic† 34 (24–54) 34 (17–47) 44 (28–54) <0.001

History of PCI‡ 538 (23.0) 244 (15.0) 294 (38.0) <0.001

History of MI‡ 358 (15.0) 110 (7.0) 248 (33.0) <0.001

History of heart failure‡ 245 (10.0) 113 (7.0) 132 (17.0) <0.001

Presenting reasons

Chest pain 1,303 (55.0) 885 (56.0) 418 (55.0) 0.60

Dyspnea or fatigue on exertion 509 (22.0) 338 (21.0) 171 (22.0) 0.59

Abnormal ECG 159 (6.8) 99 (6.3) 60 (7.8) 0.16

Arrhythmias 154 (6.6) 122 (7.7) 32 (4.2) 0.001

Syncope 50 (2.0) 30 (1.9) 20 (2.6) 0.29

Peripheral edema 6 (0.3) 4 (0.3) 2 (0.3) 1.00

Abnormal stress nuclear imaging 16 (0.7) 12 (0.8) 4 (0.5) 0.60

Abnormal stress echocardiography 29 (1.2) 19 (1.2) 10 (1.3) 0.84

Abnormal exercise stress test 10 (0.4) 8 (0.5) 2 (0.3) 0.51

Other symptoms and/or reasons 113 (4.8) 67 (4.2) 46 (6.0) 0.06

Stress CMR

Scanner field strength

1.5-T 1,535 (65.0) 1,054 (67.0) 481 (63.0) 0.07

3.0-T 814 (35.0) 529 (33.0) 285 (37.0)

CMR manufacturers§

Siemens 1,615 (69.0) 996 (63.0) 619 (81.0) <0.001

General Electric 512 (22.0) 427 (27.0) 85 (11.0)

Phillips 221 (9.0) 159 (10.0) 62 (8.0)

LVEF, % 63 (54–70) 65 (58–72) 57 (46–66) <0.001

LVEDVI, ml/m2 64 (50–79) 60 (48–73) 71 (57–89) <0.001

LVESVI, ml/m2 22 (16–32) 20 (15–28) 28 (20–44) <0.001

Inducible ischemia 405 (17.0) 0 (0.0) 405 (53.0) <0.001

MI 571 (24.0) 0 (0.0) 572 (75.0) <0.001

Values are median (IQR), mean � SD, or n (%). *Full risk factor profile missing for 123 patients. †CAD Consortium score missing for 332 patients. ‡History of PCI, MI, and CHFmissing for 5, 17, and 4 patients, respectively. §Manufacturer information missing for 1 patient.

BMI ¼ body mass index; CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance imaging; ECG ¼ electrocardiogram; IQR ¼ interquartile range; LGE ¼ lategadolinium enhancement; LVEF ¼ left ventricular ejection fraction; LVEDVI ¼ left ventricular end-diastolic volume index; LVESVI ¼ left ventricular end-systolic volume index;MI ¼ myocardial infarction; PCI ¼ percutaneous coronary intervention.

Kwong et al. J A C C V O L . 7 4 , N O . 1 4 , 2 0 1 9

Stress CMR Registry for Prognosis and Costs in the United States O C T O B E R 8 , 2 0 1 9 : 1 7 4 1 – 5 5

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and abnormal troponins with temporal changesconsistent with myocardial injury. The cutoff levelsof troponins were according to the specifications atthe individual centers. Hospitalization for unstableangina was defined as an unscheduled hospitalizationdue to worsening chest pain or anginal equivalent,combined with evidence of ischemia by imaging orsignificant coronary stenosis by computed tomogra-phy or XCA. Heart failure hospitalization was definedas an unscheduled hospitalization due to worsening

or new symptoms and/or signs of heart failure, >24 hof in-hospital stay, and intensification of heart failuretreatment. Late unplanned CABG was defined asCABG performed >6 months after the index stressCMR. CABG was included as an event because, ingeneral, it signifies the discovery of a life-threateninghigh-risk CAD state (e.g., left-main or multivesseldisease) where CABG is used as a life-saving proced-ure; this is in contrast to elective PCI procedures,which are often performed to treat non–life-

FIGURE 1 Primary and Secondary Outcome Event Rates

10.0%

8.0%

6.0%

4.0%

2.0%

12.0%

0.0%

1.2%

Ischem

ia+/LG

E–

(N = 19

4)

5.2%

1.9%

Ischem

ia–/LG

E+

(N = 361)

5.1%

0.6%

Ischem

ia–/LG

E–

(N = 1,5

83)

1.7%

4.5%

Ischem

ia+/LG

E+

(N = 211)

10.1%10.0%

8.0%

6.0%

4.0%

2.0%

12.0%

0.0%

2.9%

Moderate

Ischem

ia

(N = 12

8)

9.7%

2.9%

Mild Isc

hemia

(N = 17

5)

6.8%

0.9%

No Ischem

ia

(N = 1,9

44)

2.3%

3.1%

Severe

Ischem

ia

(N = 10

2)

6.9%

Primary Outcome Secondary Outcome

Annualized rates of primary and secondary outcomes, stratified by presence and/or absence of ischemia and left gadolinium enhancement (LGE) (left) and extent of

ischemia (right).

J A C C V O L . 7 4 , N O . 1 4 , 2 0 1 9 Kwong et al.O C T O B E R 8 , 2 0 1 9 : 1 7 4 1 – 5 5 Stress CMR Registry for Prognosis and Costs in the United States

1745

threatening CAD (e.g., relief of angina). For eitherprimary or secondary outcome, only the first eventwas counted when multiple events occurred in asubject. A successful follow-up was defined asachieving an assessment of all outcome events for $4years after the index CMR. End of follow-up datacollection and locking of database occurred onMay 25, 2018.

COSTS OF CARDIAC ISCHEMIA TESTING AFTER INDEX

STRESS CMR. All enrolling centers collected perfor-mance of all ischemia testing including stress single-photon emission computed tomography, coronarycomputed tomographic angiography, stress echocar-diography, exercise treadmill test, repeat stress CMR,and XCA during the study follow-up period. As shownin Online Table 1, the corresponding costs of theseprocedures were determined based on publishedaverage national payment rates from the MedicareHospital Outpatient Prospective Payment System,specific to the technical component of the mostcommon Healthcare Common Procedure Coding

System code and the year of the procedure. For pay-ment rates of any procedures that were not publishedin 2008 to 2010, the corresponding 2011 paymentrates were used. Procedure-specific costs and totalcardiac testing cost were calculated by adding up theestimated Medicare payments for each procedure andfrom all procedures, respectively, then expressingthem as costs per patient-years. Costs due to com-plications of test procedures, including cancersrelated to medical radiation, were not collected. Pa-tients with <90 days of follow-up were excluded fromthis analysis.

STATISTICAL ANALYSIS. Continuous variables werecompared by Student’s t-test or analysis of varianceand categorical variables by chi-square test asappropriate. Annualized event rates were calculatedby dividing the number of patients who experiencedthe event by patient-years of follow-up. We used aFine and Gray competing risk model to characterizeall cumulative incidence functions for the primaryand secondary outcomes, accounting for the effects of

FIGURE 2 Primary Outcome Over Years of Follow-Up

Ischemia+/LGE–Ischemia–/LGE+Ischemia–/LGE– Ischemia+/LGE+

6.0%

4.0%

7.0%

8.0%

5.0%

3.0%

2.0%

1.0%

0.0%Year 1

0.7%

3.1%

1.9%

4.3%

Year 4

0.3%

1.6%1.4%

4.3%

Year 3

0.6%

0.0%

0.8%

2.4%

Year 2

0.6%

1.6%

2.2%

3.3%

Year 5

1.4%

0.0%

3.6%

8.5%9.0%

Occurrence of primary outcome across different years of study follow-up, stratified by presence and/or absence of ischemia and left

gadolinium enhancement (LGE).

Kwong et al. J A C C V O L . 7 4 , N O . 1 4 , 2 0 1 9

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1746

competing risks from noncardiovascular deaths (13).We first constructed multivariable clinical models, forprimary and secondary outcomes, respectively, byincluding all clinical covariates with p < 0.1 on uni-variable screening and <10% imputed or missingdata. Presence (þ) or absence (�) of ischemia and LGEwere then added separately to each clinical model todetermine whether they each provided incrementaland independent prognostic value adjusted to thecovariates in the models. Cumulative incidencecurves were generated by plotting cumulative inci-dence of primary or secondary outcome by time offollow-up. Proportional hazards assumption was thenevaluated using visual inspection of the log-log sur-vival curves and the Schoenfeld residuals test. Allstatistical analyses were performed using SASversion 9.4 (SAS Institute, Cary, North Carolina) andp < 0.05 was used to establish statistical significance.

RESULTS

BASELINE PATIENT DEMOGRAPHICS AND CMR

CHARACTERISTICS. A total of 2,370 patients from 13participating centers and 11 states met inclusion andexclusion criteria. Of these, 21 patients (0.9%)had incomplete studies (missing or nondiagnostic

perfusion or LGE images), and the remaining 2,349patients formed the cohort. Patient demographics aresummarized in Table 1. Practice environments of theparticipating centers included university hospitals(n ¼ 7), cardiovascular group practices (n ¼ 2), mul-tispecialty practices (n ¼ 2), and U.S. government ormilitary hospitals (n ¼ 2). Primary indication for stressCMR included chest pain (55%), dyspnea (22%),changes on resting electrocardiogram suspicious ofischemia (7%), syncope or cardiac dysrhythmias (9%),and others (7%). Symptoms of patients with changeson resting electrocardiogram as the primary indica-tion were not known. The mean age in the cohort was63 � 11 years with 47% of the cohort was female.There was a high prevalence of hypertension (78%)and dyslipidemia (70%). Median number of cardiacrisk factors was 3 (interquartile range: 2 to 4). A his-tory of MI and PCI were present in 15% and 23% of thecohort, respectively. Median basic CAD ConsortiumScore (14) was 34% (mean 38 � 20%), which is indic-ative of an average intermediate pre-test likelihood ofCAD. A 3-T scanner was used in 35% and magneticresonance imaging vendors included all 3 topmanufacturers (Siemens Healthineers, Erlangen,Germany: 69%; General Electric Healthcare, Prince-ton, New Jersey: 22%; and Philips Medical Systems,

FIGURE 3 Need for Coronary Revascularization

Ischemia+/LGE–Ischemia–/LGE+Ischemia–/LGE– Ischemia+/LGE+

30%

20%

35%

40%

25%

15%

10%

5%

0%1%

18%

3%

33%

1% 1%1%3%

1% 2%2%4%

1%2%

4% 3%3%

23%

6%

38%

1%3%

1% 1%

Year 190 Days Year 3Year 2

Need for Coronary Revascularization Across Years of Follow-Up

Year 4 Year 5

45%

Occurrence of coronary revascularization across different years of study follow-up, stratified by presence and/or absence of ischemia and left

gadolinium enhancement (LGE).

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Amsterdam, the Netherlands: 9%). Gadolinium-based contrast agents included gadopentetate–diethylenetriamine pentaacetic acid (Magnevist,Bayer AG, Leverkusen, Germany) in 1,457 (62%),gadodiamide (Omniscan, GE Healthcare) in 400 (17%),gadobenate (Multihance, Bracco Diagnostics, Milan,Italy) in 246 (10.5%), gadoversetamide (Optimark,Guerbet, Villepinte, France) in 150 (6.4%), gadoter-idol (Prohance, Bracco Diagnostics) in 91 (3.9%), andgadobutrol (Gadavist, Bayer AG) in 5 patients (0.2%).Average left ventricular size and function were withinnormal limits. Ischemia and LGE were present in 17%and 24% of patients, respectively, and 14% (of 24%) ofthe patients with LGE had no clinical history of MI.Overall, 766 patients (33%) had an abnormal stressCMR, defined as the presence of either ischemia orLGE. Within the 766 patients, 194 (8%) had ischemiabut no LGE, 361 (15%) had LGE but no ischemia, and211 (9%) had both ischemia and LGE. In this cohort, 40patients (1.7%) were diagnosed to have non-CADcardiac conditions on CMR. These included 3 newcases of cardiac amyloidosis, 5 cases of hypertrophiccardiomyopathy, 5 cases of myocarditis, 5 cases ofnonischemic dilated cardiomyopathy, 8 cases of

pericardial disease, 1 case of cardiac sarcoidosis, and13 cases of nonspecific myocardial fibrosis. Apart fromthese conditions, 339 (14%) were found to have LGEconsistent with unrecognized MI.CMR PROGNOSIS FOR PRIMARY AND SECONDARY

OUTCOME. Successful follow-up of $4 years wasachieved in 2,294 patients (97.7%) with a medianfollow-up of 5.5 years (interquartile range: 4.6 to 6.8years). During study follow-up, 255 patients (11%)died with 74 (3.2%) due to cardiovascular causes and181 (7.7%) noncardiovascular causes. Primaryoutcome occurred in 153 patients including, as a firstevent, 87 nonfatal MI and 66 cardiovascular deaths.Sixty-two of the nonfatal MI and 45 of the cardio-vascular deaths occurred within the first 4 years offollow-up. Secondary outcome occurred in 374 pa-tients including, as a first event, 77 nonfatal MI, 124hospitalizations for unstable angina, 86 hospitaliza-tions for heart failure, 44 cases of late unplannedCABG, and 43 cardiovascular deaths. Primary outcomerates, expressed as percentage per patient-year,stratified by CMR findings of ischemia and LGE, areshown in Figure 1. Among the 1,583 patients (67%)who had no ischemia and no LGE (ischemia�/LGE�),

CENTRAL ILLUSTRATION Stress Cardiac Magnetic Resonance Imaging Registry for Prognosis and Costs in theUnited States

0.2

0.3

Primary Outcome Secondary Outcome

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Years of Follow-Up Years of Follow-Up

Kwong, R.Y. et al. J Am Coll Cardiol. 2019;74(14):1741–55.

Cumulative incidence functions for primary and secondary outcomes derived from a Fine and Gray competing risk model accounting for noncardiovascular death as a

competing risk event. The top panels were stratified by presence and/or absence of ischemia and late gadolinium enhancement, and the bottom panels were stratified

by the extent of ischemia.

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primary and secondary outcome occurred at low ratesof 0.6% and 1.7% per patient-year, respectively. Incontrast, those with ischemiaþ and LGEþ experi-enced rates of 4.5% and 10.1% per patient-year,respectively. Patients with no, mild, moderate, andsevere ischemia extent experienced primary outcomerates at 0.9%, 2.9%, 2.9%, and 3.1%, respectively; andsecondary outcome rates at 2.3%, 6.8%, 9.7%, and6.9%, respectively. During the first 4 years of follow-up, presence of ischemia was associated with an odds

ratio of 4.2 for acute MI (p < 0.0001) and 2.4 forcardiovascular death (p ¼ 0.004). Figure 2 demon-strates the primary outcome rates stratified by thetime period of follow-up, year 1 through year 5. Pa-tients with ischemia�/LGE� experienced low primaryoutcome rates from year 1 to year 4 (0.3% to 0.7%/year) and at 1.4% in year 5. In contrast, those withischemiaþ/LGEþ experienced the highest primaryoutcome rates across all 5 years (ranging from 2.4% to8.5%). Online Figure 1 demonstrates the secondary

TABLE 2 Univariable Association of Clinical and Stress CMR Indices With Outcome Using

a Fine and Gray Competing Risk Model

Primary Outcome Secondary Outcome

HR (95% CI) p Value HR (95% CI) p Value

Demographics

Age, per yr 1.01 (1.00–1.03) 0.06 1.01 (1.00–1.02) 0.10

Female 0.58 (0.42–0.81) 0.002 0.79 (0.64–0.97) 0.02

BMI, per kg/m2 1.00 (0.98–1.02) 0.89 1.00 (0.99–1.02) 0.76

Cardiac risk factors

Hypertension 1.53 (0.98–2.39) 0.06 2.05 (1.50–2.79) <0.0001

Hypercholesterolemia 1.02 (0.72–1.45) 0.90 1.23 (0.97–1.54) 0.09

Diabetes mellitus 1.67 (1.21–2.31) 0.002 1.51 (1.23–1.87) <0.001

Smoking 1.82 (1.32–2.51) <0.001 1.56 (1.27–1.93) <0.0001

Family history of CAD 0.75 (0.52–1.08) 0.12 1.00 (0.80–1.25) 0.98

Number of cardiac risk factors 1.36 (1.19–1.56) <0.0001 1.40 (1.29–1.53) <0.0001

CAD Consortium score, basic 1.02 (1.01–1.03) <0.0001 1.01 (1.01–1.02) <0.0001

History of PCI 2.73 (1.98–3.76) <0.0001 2.48 (2.02–3.06) <0.0001

History of MI 4.26 (3.08–5.88) <0.0001 2.79 (2.23–3.48) <0.0001

History of CHF 3.71 (2.60–5.30) <0.0001 2.72 (2.12–3.48) <0.0001

Stress CMR

LVEF, per % D 0.97 (0.96–0.98) <0.0001 0.97 (0.96–0.98) <0.0001

LVEDVI, per ml/m2 D 1.01 (1.01–1.02) <0.0001 1.01 (1.01–1.02) <0.0001

LVESVI, per ml/m2 D 1.02 (1.01–1.02) <0.0001 1.01 (1.01–1.02) <0.0001

Ischemiaþ 3.41 (2.46–4.73) <0.0001 3.30 (2.67–4.08) <0.0001

Extent of ischemia,per segment

1.10 (1.07–1.14) <0.0001 1.11 (1.08–1.14) <0.0001

LGEþ 4.10 (2.97–5.65) <0.0001 3.24 (2.64–3.97) <0.0001

Extent of LGE, per segment 1.11 (1.08–1.14) <0.0001 1.09 (1.07–1.11) <0.0001

Abnormal CMR, ischemia or MI 3.85 (2.77–5.36) <0.0001 3.59 (2.91–4.42) <0.0001

Primary outcome was defined as cardiovascular death or nonfatal MI. Secondary outcome was defined by acomposite of cardiovascular death, nonfatal MI, hospitalization for unstable angina or CHF, and late unplannedcoronary arterial bypass surgery.

þ ¼ present; D ¼ difference; CHF ¼ congestive heart failure; CI ¼ confidence interval; HR ¼ hazard ratio; otherabbreviations as in Table 1.

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outcome rates by status of ischemia and LGE in asimilar format. Patients with ischemia�/LGE� expe-rienced the lowest secondary events rates. Figure 3demonstrates the need for coronary revasculariza-tion in the whole cohort, stratified by the time pe-riods of follow-up. In patients with ischemia�/LGE�,coronary revascularization was needed in 3% in year 1and in 1% for each of the subsequent years. Mostcoronary revascularization in patients withischemiaþ/LGEþ occurred in the first 90 days.

The Central Illustration demonstrates event-freesurvival with 95% confidence intervals, based on cu-mulative incidence function for primary and sec-ondary outcome and stratified by ischemia and LGE.Stratified by ischemia and LGE, patients in theischemiaþ/LGEþ group had the highest cumulativeincidence of primary and secondary outcomes overtime, whereas in contrast patients in the ischemia�/LGE� group had the lowest incidence. Patients withischemiaþ/LGE� had incidence of primary and sec-ondary outcomes over time that were not statisticallydifferent from patients with ischemia�/LGEþ. Therewas progressively higher incidence over time withgreater extent of ischemia, for either primaryoutcome or secondary outcome, although there wasstatistical overlap between the moderate and severecategories toward primary outcome. Univariable an-alyses associating patient and CMR characteristicswith primary and secondary outcome are presentedin Table 2. For primary outcome, age, smoking, his-tory of hypertension, diabetes, history of MI, historyof PCI, history of congestive heart failure, and leftventricular end-systolic volume index were thestrongest set of clinical covariates selected fromunivariable screening in forming the clinical modelfor the primary outcome (�2 log L: 1,950). Table 3demonstrates the multivariable clinical models ofprimary and secondary outcome. Presence ofischemia and presence of LGE independentlyimproved this clinical model for primary outcomewhen they were separately added (�2 log L: 1,933 and1,939, for ischemia and LGE, respectively, bothp < 0.0001) or when both added (�2 log L: 1,927) tothe model. Adjusted to the effects of the covariates inthe clinical model and to each other, presence ofischemia and presence of LGE both maintained sig-nificant association with primary outcome (adjustedhazard ratio: 1.96; 95% confidence interval: 1.35 to2.86; p ¼ 0.0004; and adjusted hazard ratio: 1.64; 95%confidence interval: 1.08 to 2.51; p ¼ 0.02, respec-tively). Similar significant association was observedfor presence of ischemia and LGE with secondaryoutcome. Both ischemia presence and extent alsodemonstrated strong association with all-cause death

or nonfatal MI (hazard ratios: 1.84 and 1.28, respec-tively, both p < 0.0001). Visual inspection of the log-log survival curves and calculation of the Schoenfeldresiduals showed that the proportionality assumptionwas not violated.UTILIZATION OF INVASIVE TESTING AND CORONARY

REVASCULARIZATION AFTER CMR. Referrals to inva-sive XCA and performance of coronary revasculari-zation at 90 days after CMR per discretion of theprimary caring team, stratified by ischemia and LGEand ischemia extent, are shown in Figure 4. Only 4%of patients with ischemia�/LGE� were referred toundergo CA, which compared with 46% among pa-tients with ischemiaþ/LGEþ, with the presence ofischemia being a key factor for referral to CA. Proba-bilities of coronary revascularization procedure(either PCI or CABG), once referred to CA, rangedfrom 24% in the ischemia�/LGE� group to 73% in theischemiaþ/LGEþ group. Increasing extent of ischemiawas associated with stepwise higher likelihood ofreferral to CA and coronary revascularization.

FIGURE 4 Invasive

60%

40%

70%

50%

30%

20%

10%

0%

4%

80%

IscheLG

Referral to invasive c

revascularization (Re

TABLE 3 Multivariable Models for Primary and Secondary Outcomes Using a Fine and Gray Competing Risk Model

Primary Outcome Secondary Outcome

ParameterEstimate p Value HR (95% CI)

ParameterEstimate p Value HR (95% CI)

Age, per yr 0.02 0.08 1.02 (1.00–1.03) 0.01 0.12 1.01 (1.00–1.02)

History of

PCI 0.37 0.09 1.45 (0.95–2.22) 0.49 0.0004 1.63 (1.25–2.14)

MI 0.72 0.003 2.05 (1.28–3.28) 0.29 0.07 1.34 (0.98–1.82)

CHF 0.65 0.01 1.92 (1.17–3.15) 0.50 0.004 1.65 (1.17–2.32)

Diabetes 0.30 0.10 1.35 (0.94–1.94) 0.22 0.07 1.24 (0.99–1.57)

Hypertension 0.17 0.46 1.19 (0.75–1.89) 0.55 0.001 1.73 (1.24–2.42)

Tobacco use 0.48 0.006 1.62 (1.15–2.28) 0.31 0.006 1.37 (1.09–1.71)

LVESVI, ml/m2 0.01 0.09 1.01 (1.00–1.01) 0.01 0.02 1.01 (1.00–1.01)

LGEþ 0.50 0.02 1.64 (1.08–2.51) 0.48 0.0005 1.62 (1.23–2.12)

Ischemiaþ 0.67 0.0004 1.96 (1.35–2.86) 0.73 <0.0001 2.08 (1.62–2.67)

Primary outcome was defined as cardiovascular death or nonfatal MI. Secondary outcome was defined by a composite of cardiovascular death, nonfatal MI, hospitalization forunstable angina or CHF, and late unplanned coronary arterial bypass surgery.

Abbreviations as in Tables 1 and 2.

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COSTS SPENT ON ISCHEMIA TESTING DURING

STUDY FOLLOW-UP. During follow-up, 142 stressechocardiography, 808 stress single-photon emissioncomputed tomography, 199 coronary computedtomographic angiography, 149 repeat stress CMR, 215

XCA and Revascularization at 90 Days

24%

38%

46%

10%

33%

46%

73%

Ischemia+/LGE–

Ischemia–/LGE+

mia–/E–

Ischemia+/LGE+

60%

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Referred to CA Within 90 Days Coronary Rev

oronary angiography (XCA) at 90-day post-stress cardiac magnetic resonanc

vasc), stratified by presence and/or absence of ischemia and left gadolinium

exercise treadmill, and 915 XCA clinical examinationswere performed. Figure 5 illustrates the average cost(US$/patient) spent on ischemic testing according tofollow-up periods. Between the 4 CMR result groups,those with ischemia�/LGE� had the lowest cost

5%

27%

48%

66%

30%

50%

56%

67%

ModerateIschemia

MildIschemia

NoIschemia

SevereIschemia

asc Within 90 Days if Referred to CA

e imaging with corresponding proportion of patients undergoing

enhancement (LGE) (left) and extent of ischemia (right).

FIGURE 5 Costs of Ischemia Testing

X-Ray Coronary AngiographyCTA

Exercise Treadmill TestStress Nuclear

Stress CMRStress Echo

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Costs of downstream cardiac tests incurred during follow-up, stratified by stress cardiac magnetic resonance imaging (CMR) findings with breakdown by modality.

Costs are in U.S. dollars spent per patient. CTA ¼ computed tomography angiography; LGE ¼ late gadolinium enhancement.

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spending across all periods of follow-up. During thefirst 90 days after CMR, patients with ischemiaþ/LGEþ incurred approximately 10-fold higher coststhan did those with ischemia�/LGE� in the same timeperiod ($585 vs. $54, p < 0.0001) due to the referral toXCA. Whereas XCA contributed the most to overallcosts during the first year in patients with ischemiaþand to a lesser degree those with ischemia�/LGEþ,stress single-photon emission computed tomographycontributed the most in later years across all groups.

PATTERNS ACROSS DIFFERENT PRACTICE SETTINGS.

Characteristics of the enrolling centers are shown inOnline Table 2. University hospitals (n ¼ 7), cardio-vascular group practices (n ¼ 2), multispecialty prac-tices (n ¼ 2), and U.S. government or militaryhospitals (n ¼ 2) enrolled 1,019 patients (43%), 464(20%), 610 (26%), and 256 (11%), respectively. Over 4years after CMR, 188 patients (8%), 81 (3.5%), and 15(0.6%) had PCI, CABG, and both, respectively.Figure 6 illustrates the performance of invasive XCAat 90 days, by practice types and CMR findings.Across all practice types, patients with ischemia�/LGE� were referred to undergo XCA at 90 days at lowrates (2.8% to 4.9%). Patients with ischemiaþ un-derwent XCA at substantially higher rates across allpractice types, the highest at 62% by the government/military hospital group. As illustrated in OnlineFigure 2, costs spent at 1 year demonstrated a

similar pattern across the practice types andCMR findings.

CONCORDANCE RATES BETWEEN ENROLLING

CENTERS AND THE IMAGING CORE LABORATORY.

Images from 235 studies (10%) were interpreted bythe CMR core lab blinded to clinical characteristicsand outcomes. The concordance rates of centersversus core lab interpretation on ischemia presence,ischemia grade, LGE presence, and LGE grade were82%, 86%, 90%, and 92%, respectively.

DISCUSSION

SPINS is the largest multicenter study in the UnitedStates to date evaluating the prognostic value of stressCMR in patients presenting with stable chest painsyndromes. The study comprised a consecutive cohortfrom centers with diverse practice settings with afollow-up target of 4 years achieved in >97% of pa-tients. There are 3 key findings (Central Illustration).First, in this cohort with an intermediate pre-testlikelihood of CAD and a median basic consortiumscore of 34%, 67% of the study cohort had ischemia�/LGE� and experienced low annual rate of primaryand secondary outcomes after CMR (0.6% and1.7%, respectively), which is in contrast to thepatients with ischemiaþ/LGEþ (4.5% and 10.1%,respectively). Second, the need for referral to

FIGURE 6 Invasive XCA at 90 Days, Stratified by Practice Types

X-Ray Coronary Angiography at 90 Days,by Practice Types and CMR Results

Ischemia+/LGE–Ischemia–/LGE+Ischemia–/LGE– Ischemia+/LGE+

50.0%

30.0%

60.0%

40.0%

20.0%

10.0%

0.0%Cardiovascular

Group

50.0%

25.0%

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41.2%

62.0%58.3%

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10.5%

4.9%

10.9%

31.3%

41.3%

4.2%7.4%

2.8%

Government orMilitary

Multi-SpecialtyGroup

University Hospitals

70.0%

Referral to invasive XCA at 90-day post stress CMR, stratified by presence and/or absence of ischemia and LGE, according to practice

environment. Abbreviations as in Figures 1, 4, and 5.

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coronary revascularization was low for patients withischemia�/LGE�, at 3% in the first year and <1% ineach of the subsequent 3 years, compared with 38%and 3% for patients with ischemiaþ/LGEþ. Third, pa-tients with ischemia�/LGE� had low average annualcosts spent on downstream ischemia testing across allyears of follow-up, and this finding is consistent acrosspractice types of the participating sites in the UnitedStates.

As a gate-keeping noninvasive test, it is importantthat a “low-risk” population be identified therebyavoiding unnecessary downstream tests and invasivetreatment. From a cohort of 3,647 patients, themultinational EuroCMR (European CardiovascularMagnetic Resonance) registry reported a negativecardiovascular event rate as low as 1% per year,demonstrating that stress CMR was effective inobviating the need for invasive angiography (15,16).The Italian STRATEGY (Stress Cardiac MagneticResonance Versus Computed Tomography CoronaryAngiography for the Management of SymptomaticRevascularized Patients) study observed that stress

CMR has higher cost-effectiveness than coronarycomputed tomography angiography in assessingsymptomatic patients with a history of coronaryrevascularization (17). SPINS extended currentknowledge by examining the roles of stress CMR inthe U.S. health care system. Apart from low incidenceof primary and secondary outcomes, patients withoutischemia or LGE by CMR had low downstream needfor coronary revascularization and incurred low costsfor CAD testing throughout study follow-up. StressCMR is currently underutilized for chest pain assess-ment compared with other noninvasive methods inthe United States; however, the performance charac-teristics observed in SPINS strongly support the use ofstress CMR as an effective gatekeeping strategy forinvasive angiography.

It is increasingly recognized that the presence ofscar independently predicts adverse outcomes in CAD(18). Studies have shown that CMR has excellentsensitivity in detecting subendocardial infarctions(19). In SPINS, the presence of either inducibleischemia or LGE was independently associated with

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higher primary and secondary events. In addition, theeffects of inducible ischemia and LGE were additive,such that patients with both findings were at thehighest risk. CMR also allows for the detection of un-recognized MI, which is of prognostic importance. In alarge study of older community dwellers in Iceland,the rate of unrecognizedMI by CMRwas 17% (20). Overlong-term follow-up, unrecognized MI by CMR wasassociated with increased all-cause mortality. In ourstudy, although the prevalence of MI by LGE was 24%,themajority (14%) did not have any prior history of MI,highlighting the diagnostic importance of CMR.

In the current era of intense debate betweenanatomical and functional testing in stable CAD, 2large randomized trials have compared coronarycomputed tomographic angiography to stress testing(21,22). The PROMISE (Prospective Multicenter Im-aging Study for Evaluation of Chest Pain) and SCOT-HEART (Scottish Computed Tomography of theHeart Trial) studies, however, included relativelylow-risk patients and did not include stress CMR aspart of their diagnostic strategies. Given its consistentnegative predictive value demonstrated in SPINS andEuroCMR (16) and its lack of ionizing radiationexposure, CMR is a practical choice when consideringstress testing. The MR-IMPACT (Magnetic ResonanceImaging for Myocardial Perfusion Assessment inCoronary Artery Disease Trial) I and II studies arecurrently the largest prospective multicenter trialsthat have included stress CMR (1,3). These studiesand CE-MARC (Clinical Evaluation of Magnetic Reso-nance Imaging in Coronary Heart Disease) focused onthe diagnostic accuracy of CMR (23), whereas CE-MARC 2 examined CMR’s impact on downstreamangiography use (24). The recently presented MR-INFORM (MR Perfusion Imaging to Guide Manage-ment of Patients With Stable Coronary Artery Disease)study compared stress CMR with anatomic assess-ment using XCA with fractional flow reserve in 918symptomatic patients at high pre-test probability ofCAD (25). In this 1:1 randomized control trial, themajor adverse cardiac event rate was similar in bothstrategies at 1-year follow-up.

Health care payers and patients are increasinglyaware of the cost burden from repeat cardiac testing innoninvasive cardiovascular imaging. With the currentfocus on value-based care, few studies have thus farexamined the downstream clinical and economicvalues of stress CMR. In the current SPINS cohort,downstream rate of coronary revascularization byeither PCI or CABG was the highest among patientswith ischemiaþ/ LGEþ. On the other hand, those withischemia�/LGE� by CMR had very low spending rates

for ischemia testing or coronary revascularization. Ourresults are congruent with the cost-minimization re-sults of the EuroCMR registry (16).STUDY LIMITATIONS. First, given the retrospectivedesign of this study, we could not capture all thedirect therapeutic and management decisions madeat the time of the CMR study. Second, CMR studieswere performed in a clinical setting so we cannotdetermine whether any knowledge of coronary anat-omy from prior angiography could have influencedthe CMR interpretations. Third, our participating siteswere predominantly tertiary-care experienced cen-ters, therefore, there may have been a local referralbias of higher-risk patients to CMR, and uncertaintyexists whether the current results generalize to lessexperienced centers. Fourth, the SPINS study wasconducted at a time when quantitation of CMRperfusion, LGE size, and invasive fractional flowreserve were not performed as a clinical routine, thus,these factors, which are relevant to today’s practice,therefore could not be accounted for. Fifth, core labassessment of 10% of the images for ischemia andLGE presence resulted in only a modest concordancerate. Given the retrospective study design aimed atcapturing the clinical consequences of local inter-pretation at time of CMR performance, there was noattempt to standardize reading or interpretationprocedures between the enrolling centers and thecore lab. Finally, our study is not able to assess CMRguidance of coronary revascularization towardimproving patient outcome, given its nonrandomizedstudy design and limited study power. This non-randomized study design without a comparativeimaging-based strategy also prohibited any conclu-sions in causal estimates or comparison against keyalternative methods in this setting. These limitationswill need to be addressed in prospective random-ized trials.

CONCLUSIONS

Among patients with stable intermediate-risk chestpain syndromes, a stress CMR without evidence ofischemia or LGE was associated with very low inci-dence of adverse cardiac events and low health carecosts spent on downstream cardiac testing.

ADDRESS FOR CORRESPONDENCE: Dr. Raymond Y.Kwong, Brigham and Women’s Hospital, Cardiovas-cular Division, Department of Medicine, HarvardMedical School, 75 Francis Street, Boston, Massa-chusetts 02115. E-mail: rykwong@bwh.harvard.org.Twitter: @BrighamWomens.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: CMR

stress perfusion imaging can identify patients with chest

pain who are at risk of ischemic events and guide referral

for coronary revascularization. Implementation of stress

CMR as an initial diagnostic modality may prove less

costly than conventional strategies.

TRANSLATIONAL OUTLOOK: Future studies should

compare the cost and value of stress CMR with other

noninvasive modalities in the evaluation of patients with

suspected ischemic heart disease.

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RE F E RENCE S

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KEY WORDS cost of care, prognosis, stresscardiac magnetic resonance imaging

APPENDIX For supplemental figures andtables, please see the online version ofthis paper.